Study redefines early treatment of Crohn’s disease and improves outcomes

1st March 2024

Top-down treatment with infliximab plus an immunomodulator substantially improves outcomes for patients with newly diagnosed Crohn’s disease compared with accelerated step-up therapy, UK research finds.

Previous trials had supported earlier use of anti-tumour necrosis factor therapy, usually in combination with an immunomodulator, researchers wrote in The Lancet Gastroenterology and Hepatology.

However, the most common strategy in the UK and globally was an accelerated step-up approach, where treatment is escalated until the tendency to relapse is controlled, they said.

The multi-centre PROFILE trial enrolled 386 patients aged 16-80 years with newly diagnosed, active Crohn’s disease, who had raised C-reactive protein, calprotectin of 200 μg/g or more, plus active inflammation on ileo-colonoscopy.

Patients were stratified based on a blood-based biomarker previously found to correlate with the need for future treatment escalation and then randomised to either top-down therapy or the accelerated step-up approach.

Over 48 weeks off follow-up, the biomarker did not show any clinical utility.

However, 79% of patients achieved sustained steroid-free and surgery-free remission in the top-down group, compared with 15% in the conventional therapy group, a 64-percentage point difference, they reported.

‘Top-down treatment also showed greater efficacy in achieving endoscopic remission, improved quality of life, and reduced number of flares requiring treatment escalation,’ they wrote.

It was also safer than conventional therapy for Crohn’s disease, with fewer adverse and serious adverse events and no increased rate of infection. 

A reduced need for urgent abdominal surgery was also found, with one person in the top-down group requiring surgery for complications, compared with 10 people in the step-up group, they added. 

‘These findings are potentially transformative for the management of Crohn’s disease,’ the study authors concluded. 

‘While PROFILE did not identify a clinically useful biomarker, it has provided clear evidence with regards to optimal treatment strategy from diagnosis.’

First author Dr Nuru Noor, of the Department of Medicine at the University of Cambridge, said the study findings redefined what should be considered as early treatment for Crohn’s disease.

‘Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore “good enough”,’ he said.

‘As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking – and has likely been ticking for some time – in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible.’

Chief investigator Professor Miles Parkes, who is director of the NIHR Cambridge Biomedical Research Centre, said the study showed clinicians could prevent most adverse outcomes for Crohn’s disease, including need for urgent surgery, with a treatment strategy that was safe and becoming increasingly affordable.

‘If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer “top-down” therapy straight after diagnosis rather than having to wait and use “step-up” treatment,’ he said.

In February 2023, the Medicines and Healthcare products Regulatory Agency approved upadacitinib for use in patients with moderate to severely active Crohn’s disease who have had either an inadequate response, or were intolerant to, conventional therapy or a biological agent.

Risankizumab surpasses ustekinumab when head to head in Crohn‘s disease

27th September 2023

The use of risankizumab (brand name Skyrizi) in the treatment of adult patients with moderately to severely active Crohn‘s disease met the two primary endpoints in a head-to-head study compared to ustekinumab, its manufacturer AbbVie has announced.

While both risankizumab and ustekinumab are already approved for Crohn‘s disease and other conditions, their modes of action are different, with the former selectively blocking interleukin-23 (IL-23) signalling and the latter blocking both IL-12 and IL-23. The researchers therefore sought to determine if these differences affect treatment outcomes.

In the phase 3, multi-centre, randomised, head-to-head SEQUENCE study, the primary endpoint was non-inferiority for clinical remission at week 24 and superiority of endoscopic remission at week 48.

All participants had a confirmed diagnosis of Crohn‘s disease for at least three months and a Crohn‘s Disease Activity Index (CDAI) score of 220 to 450 at baseline. They were also considered to have moderate-to-severe disease based on an assessment of stool frequency, abdominal pain score, their Simple Endoscopy Score for Crohn‘s Disease (SES-CD), and a demonstrated intolerance or inadequate response to one or more anti-TNF therapies.

Participants assigned to risankizumab received a 600 mg intravenous induction at Weeks 0, 4 and 8 and 360 mg subcutaneous injection starting at week 12 and every eight weeks thereafter, through to week 48.

Risankizumab versus ustekinumab

The results of the first primary endpoint, clinical remission (per CDAI, defined as CDAI <150) at week 24, met non-inferiority of risankizumab versus ustekinumab (non-inferiority margin of 10%). Remission rates were 59% in the risankizumab group and 40% in the ustekinumab group.

For the second primary endpoint of endoscopic remission (SES-CD ≤4 and at least a two-point reduction versus baseline and no sub-score greater than 1 in any individual component) at week 48, risankizumab provided a remission rate of 32% compared to 16% in the ustekinumab group (p < 0.0001).

In a commentary of these results, Dr Laurent Peyrin-Biroulet, director of the Infinity Institute, professor of gastroenterology and head of the inflammatory bowel disease group at the gastroenterology department, University Hospital of Nancy in France, said: ‘These results add to our growing body of evidence for Skyrizi in Crohn‘s disease. This study highlights the efficacy of Skyrizi compared to ustekinumab in helping eligible patients achieve clinical and endoscopic treatment goals and also reinforces the safety profile observed in previous studies.’

Full results from the SEQUENCE study will be presented at a future medical meeting and submitted for publication in a peer-reviewed journal.

MHRA approves Rinvoq for moderate to severe Crohn’s disease

13th February 2023

Upadacitinib (brand name Rinvoq) was previously been approved for ulcerative colitis and is now licensed in moderate to severe Crohn’s disease.

The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has now approved upadacitinib for use in patients with moderate to severely active Crohn’s disease and who have had either an inadequate response or were intolerant to, conventional therapy or a biological agent.

Crohn’s disease is a form of inflammatory bowel disease that affects any part of the gastrointestinal tract and which is thought to affect around 10 million people worldwide and has a major impact on health-related quality of life.

Patients with Crohn’s will often receive oral corticosteroids to manage a disease flare, although those with more severe disease receive biologics either with or without immunomodulators to induce and maintain remission.

Upadacitinib is a Janus kinase inhibitor and a Phase II trial, evaluating the efficacy of 3 mg, 6 mg, 12 mg 24 mg twice daily or 24 mg daily, concluded that the drug induced endoscopic remission in a significant proportion of patients in comparison to placebo.

The MHRA decision was based on the findings of three other clinical studies and are reported in the press release.

In the first, U-EXCEED, a significantly higher proportion of patients treated with upadacitinib 45 mg daily achieved clinical remission per SF/AP at week 12 compared to placebo (40% vs 14%, p<0.001) and an endoscopic response compared to placebo (35% vs 4%, p<0.001).

In the second trial, U-EXCEL, again more patients given a 12-week induction regimen of upadacitinib 45 mg daily achieved clinical remission (51% vs 22%, p < 0.001) and endoscopic response (46% vs 13%, p < 0.001) compared to placebo.

In the third study, U-ENDURE which was a maintenance trial, patients who had responded to 12 weeks of upadacitinib 45 mg, were re-randomised to 15 mg, 30 mg or placebo and assessed at week 52.

The results showed that clinical remission occurred in 36 and 46% respectively (i.e., for 15 and 30 mg) compared to 14% for placebo (p < 0.001).

Similarly, endoscopic response occurred in 28 and 40% compared to 7% in the placebo group (p < 0.001).

Interestingly, a recently published real-world study of upadacitinib in patients with Crohn’s disease has shown that the drug induced subjective and objective responses in 25% and 42% of patients, respectively.

Updated information on the indications for rinvoq can be found in the summary of product characteristics.